Silencing of RhoA nucleotide exchange factor, ARHGEF3 reveals its unexpected role in iron uptake

Genome-wide association meta-analysis studies (GWAS) have identified over 100 independent genetic loci associated with blood cell indices, including volume and count of platelets and erythrocytes. Although several of these loci encode known regulators of haematopoiesis the mechanism by which the majority of sequence variants exert their effect on blood cell formation remains elusive. An example is the Rho guanine nucleotide exchange factor, ARHGEF3, which was previously implicated by GWAS in bone cell biology. Here we report on the unexpected role of ARHGEF3 in regulation of iron uptake and erythroid cell maturation. Although early erythroid differentiation progressed normally, silencing of arhgef3 in Danio rerio resulted in microcytic and hypochromic anaemia. This was rescued by intracellular supplementation of iron, demonstrating that arhgef3 depleted erythroid cells, are fully capable of haemoglobinisation. Disruption of thearhgef3 target, RhoA, also produced severe anaemia, which was again corrected by iron injection. Moreover, silencing of ARHGEF3 in erythromyeloblastoid cells K562 revealed that the uptake of transferrin was severely impaired. Taken together, this is the first study to provide evidence for ARHGEF3 being a regulator of transferrin uptake in erythroid cells, through activation of RHOA.